JARID1B-mediated epigenetic regulation of oncogenic signals in oral cancer

项目摘要 这项建议为我们惊人的观察奠定了基础，即口腔癌细胞在两种状态之间转移， 二分的PI 3 K/Akt信号和对抗PI 3 K药物的反应。具体地说，发现Akt的最大激活是 仅在肿瘤细胞的一小部分缓慢循环中，而PI 3 K/Akt信号在不同的“G 0- 比如”分数。这些G 0样细胞是非分裂的，但保留了高致瘤潜力，并显示出广泛的治疗 抵抗，包括逃避PI 3 K抑制剂。退出G 0样状态由H3 K4 me 3调节 去甲基酶JARIDB，其抑制在选择启动子处的转录，但也具有不明确的作用，包括 与其催化功能无关。G 0样细胞中的JARID 1B上调将其重新编程为慢细胞。 循环，Akt-过度活跃表型，其对PI 3 K抑制剂敏感。干细胞样特征和 这种JARID 1B高状态的增强的致瘤性暗示它允许静止细胞发挥其恶性肿瘤作用。 潜力当通过靶向PI 3 K耗尽JARID 1Bhigh细胞时，G 0样细胞仍然可以维持肿瘤生长 通过替代的JARID 1B非依赖性途径退出静止。通过这一途径，G 0样细胞可以 成为已知作为PI 3 K抑制剂基础的补偿性MAPK途径活化的关键位点 阻力因此，我们的假设是G 0样细胞由JARID 1B驱动为PI 3 K依赖性干细胞样细胞。 但在PI 3 K抑制下也绕过这种状态，以维持在 维持癌症的生长为了确定JARID 1B对G 0样细胞退出静止的贡献，我们将 描述其脱甲基酶依赖性与独立功能以及与致癌PI 3 K信号的相互作用， 促进G1-S过渡（目标1）。为了研究JARID 1B对G 0样状态的恶性潜力的贡献， 我们将研究JARID 1B通过延长S/G2来促进肿瘤侵袭行为的潜力， 间充质样分化（aim 2）。G 0样和JARID 1B高细胞的作用也将在下文中定义。 PI 3 K抑制，其中JARID 1Bhigh细胞可以通过以下途径恢复到维持口腔癌进展的G 0样状态： MAPK途径以JARID 1B非依赖性方式补偿（目的3）。了解的机制 在双重状态之间转换，其共同构成了治疗的侵袭性、难治性部分。 肿瘤细胞库，将定义新的策略，以解决治疗耐药性的表观遗传可塑性， 口腔癌

PROJECT SUMMARY This proposal pursues a basis for our striking observation that oral cancer cells transit between two states with dichotomous PI3K/Akt signals and responses to anti-PI3K drugs. Specifically, maximal Akt activation is found in only a small, slow-cycling fraction of tumor cells, whereas PI3K/Akt signals are suppressed in a distinct, "G0- like" fraction. These G0-like cells are non-dividing but retain high tumorigenic potential and show broad therapy resistance, including escape from PI3K inhibitors. Exiting the G0-like state is regulated by the H3K4me3 demethylase JARIDB, which represses transcription at select promoters but also has ill-defined roles, including ones independent of its catalytic function. JARID1B upregulation in G0-like cells reprograms them into the slow cycling, Akt-hyperactive phenotype, which is sensitive to PI3K inhibitors. The stem cell-like features and enhanced tumorigenicity of this JARID1Bhigh state implicate it in allowing quiescent cells to exert their malignant potential. When JARID1Bhigh cells are depleted by targeting PI3K, G0-like cells could still sustain tumor growth by an alternate, JARID1B-independent pathway for exiting quiescence. By this pathway, G0-like cells may become the critical locus for the compensatory MAPK pathway activation known to underlie PI3K inhibitor resistance. Thus our hypothesis is that G0-like cells are driven by JARID1B to a PI3K-dependent, stem cell-like state with aggressive features but also bypass this state under PI3K inhibition to maintain a central role in sustaining cancer growth. To determine JARID1B's contribution to G0-like cells exiting quiescence, we will delineate its demethylase dependent vs. independent functions and interaction with oncogenic PI3K signals in promoting G1-S transition (aim 1). To pursue JARID1B's contribution to the G0-like state's malignant potential, we will examine JARID1B's potential to promote aggressive tumor behavior by prolonging S/G2 while driving mesenchymal-like differentiation (aim 2). The roles of G0-like and JARID1Bhigh cells will also be defined under PI3K inhibition, where JARID1Bhigh cells may return to a G0-like state that sustains oral cancer progression via MAPK pathway compensation in a JARID1B-independent manner (aim 3). Understanding the mechanisms of transit between the dual states, which together comprise an aggressive, treatment refractory segment of the tumor cell pool, will define new strategies to address the epigenetic plasticity underlying treatment resistance in oral cancer.